Abstract Neuronal loss and cognitive dysfunction are associated with pathological formation of tau protein-containing neurofibrillary tangles (NFT). NFTs are hallmarks of all tauopathies, including Alzheimer?s disease (AD) and chronic traumatic encephalopathy (CTE). Traumatic brain injury (TBI) can trigger persistent and even progressive tauopathy in humans and laboratory animals. TBI-induced tauopathy is associated with early-onset cognitive decline and later development of AD and CTE. Transgenic mice expressing mutant human tau P301L show progressive tauopathy similar to that in human AD brains. The goal of this multi-PI project is to investigate repurposed Food and Drug Administration (FDA)-approved drugs as potential therapeutics for AD and related dementias. We will investigate drug efficacy on tau-related proteomic and neuropathological alterations induced by: (i) neurotrauma (TBI), and (ii) genetic overexpression of a pathogenic mutant human tau transgene (P301L transgenic mice). We have detected and reported significant differences in p-tau and other phospho-proteins in mice exposed to various forms of neurotrauma (blast, impact) using a multitude of techniques (neuropathology, immunoblotting, ELISA, mass spectrometry profiling). By screening angiotensin converting enzyme inhibitor (ACEI), Beta Blockers (BB), Metformin (MET), Statins (STAT) and combination therapy in over a million medical records in the VA-CDW, we found that combined treatment with small molecule drugs ACEI and STAT was associated with a longer preclinical (asymptomatic) period before AD onset compared to patients not treated with these drugs after incidents of TBI. These results inform our central hypothesis that tauopathy and related neurodegenerative disease pathologies can be suppressed in TBI-CTE and tau P301L mice treated with ACEI+STAT combination therapy. We propose three Aims to test this hypothesis. Aim 1. To search for combination of three ACEI, BB, MET or STAT or single new class of FDA-approved medications that prolong the period between incident TBI and AD onset in a large national medical record data base (VA-CDW). Aim 2. To investigate the relationship of phosphorylated tauopathy (p-tau) to neurodegeneration and axonopathy in validated mouse models of impact TBI-CTE and mutant human tau overexpression. We will quantify brain tissue levels of tau and p-tau in a validated mouse model of lateral impact-induced TBI-CTE (vs. uninjured controls) and in P301L transgenic mouse model (vs wildtype, WT), and we will analyze demyelination and microtubule instability in neurodegeneration and measure specific target proteins (e.g., Map1b, identified by proteomic analysis of TBI mouse brains). Aim 3. To suppress pathogenic tauopathy in TBI-CTE, P301L mouse brains by ACEI+STAT treatment. We will determine whether ACEI+STAT treatment reduces tau and p-tau in brains in both models compared to saline (SAL) control treatment and characterize proteomic profiles by mass spectrometry and neuropathology in brains from the treated mice.